Binding site structure of one LRP-RAP complex: Implications for a common ligand-receptor binding motif

被引:59
作者
Jensen, Gitte A.
Andersen, Olav M.
Bonvin, Alexandre M. J. J.
Bjerrum-Bohr, Ida
Etzerodt, Michael
Thogersen, Hans C.
O'Shea, Charlotte
Poulsen, Flemming M.
Kragelund, Birthe B.
机构
[1] Univ Copenhagen, SBiN Lab, Inst Mol Biol & Physiol, DK-1353 Copenhagen K, Denmark
[2] Aarhus Univ, Dept Biol Mol, Gene Express Lab, DK-8000 Aarhus C, Denmark
[3] Univ Utrecht, NMR Res Grp, Bijvoet Ctr Biomol Res, NL-3584 CH Utrecht, Netherlands
关键词
NMR; HADDOCK; lipoprotein; domain; SPR;
D O I
10.1016/j.jmb.2006.07.013
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The low-density lipoprotein receptor-related protein (LRP) interacts with more than 30 ligands of different sizes and structures that can all be replaced by the receptor-associated protein (RAP). The double module of complement type repeats, CR56, of LRP binds many ligands including all three domains of RAP and alpha(2)-macroglobulin, which promotes the catabolism of the A beta-peptide implicated in Alzheimer's disease. To understand the receptor-ligand cross-talk, the NMR structure of CR56 has been solved and ligand binding experiments with RAP domain 1 (RAPd1) have been upon complex formation, a HADDOCK model of the complex between CR56 and RAPd1 has been obtained. The binding residues are similar to a common binding motif suggested from alpha(2)-macroglobulin binding studies and provide evidence for an understanding of their mutual crosscompetition pattern. The present structural results convey simultaneous description of both binding partners of an LRP-ligand complex and open a route to a broader understanding of the binding specificity of the LRP receptor, which may involve a general four-residue receptor-ligand recognition motif common to all LRP ligands. The present result may be beneficial in the design of antagonists of ligand binding to the LDL receptor family, and especially of drugs for treatment of Alzheimer's disease. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码:700 / 716
页数:17
相关论文
共 65 条
[1]   Specific binding of α-macroglobulin to complement-type repeat CR4 of the low-density lipoprotein receptor-related protein [J].
Andersen, OM ;
Christensen, PA ;
Christensen, LL ;
Jacobsen, C ;
Moestrup, SK ;
Etzerodt, M ;
Thogersen, HC .
BIOCHEMISTRY, 2000, 39 (35) :10627-10633
[2]   Identification of the minimal functional unit in the low density lipoprotein receptor-related protein for binding the receptor-associated protein (RAP) - A conserved acidic residue in the complement-type repeats is important for recognition of RAP [J].
Andersen, OM ;
Christensen, LL ;
Christensen, PA ;
Sorensen, ES ;
Jacobsen, C ;
Moestrup, SK ;
Etzerodt, M ;
Thogersen, HC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (28) :21017-21024
[3]   Dominant thermodynamic role of the third independent receptor binding site in the receptor-associated protein RAP [J].
Andersen, OM ;
Schwarz, FP ;
Eisenstein, E ;
Jacobsen, C ;
Moestrup, SK ;
Etzerodt, M ;
Thogersen, HC .
BIOCHEMISTRY, 2001, 40 (50) :15408-15417
[4]   Analysis of a two-domain binding site for the urokinase-type plasminogen activator-plasminogen activator inhibitor-1 complex in low-density-lipoprotein-receptor-related protein [J].
Andersen, OM ;
Petersen, HH ;
Jacobsen, C ;
Moestrup, SK ;
Etzerodt, M ;
Andreasen, PA ;
Thogersen, HC .
BIOCHEMICAL JOURNAL, 2001, 357 (01) :289-296
[5]  
Brunger A. T, 1992, XPLOR 3 1 SYSTEM XRA
[6]  
Bu GJ, 2001, INT REV CYTOL, V209, P79
[7]   Role of RAP in the biogenesis of lipoprotein receptors [J].
Bu, GJ ;
Marzolo, MP .
TRENDS IN CARDIOVASCULAR MEDICINE, 2000, 10 (04) :148-155
[8]   3-DIMENSIONAL STRUCTURE OF THE 2ND CYSTEINE-RICH REPEAT FROM THE HUMAN LOW-DENSITY-LIPOPROTEIN RECEPTOR [J].
DALY, NL ;
DJORDJEVIC, JT ;
KROON, PA ;
SMITH, R .
BIOCHEMISTRY, 1995, 34 (44) :14474-14481
[9]   3-DIMENSIONAL STRUCTURE OF A CYSTEINE-RICH REPEAT FROM THE LOW-DENSITY-LIPOPROTEIN RECEPTOR [J].
DALY, NL ;
SCANLON, MJ ;
DJORDJEVIC, JT ;
KROON, PA ;
SMITH, R .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (14) :6334-6338
[10]   ACID-DEPENDENT LIGAND DISSOCIATION AND RECYCLING OF LDL RECEPTOR MEDIATED BY GROWTH-FACTOR HOMOLOGY REGION [J].
DAVIS, CG ;
GOLDSTEIN, JL ;
SUDHOF, TC ;
ANDERSON, RGW ;
RUSSELL, DW ;
BROWN, MS .
NATURE, 1987, 326 (6115) :760-765